Humans have shaped and in turn been shaped by the mighty Missouri River. There are numerous prehistoric and historic village sites within the Missouri National Recreational River boundaries. Early cultures developed along the river, most notably the Woodland Culture, dating back up to 2,500 years. They were followed by the Iowy, Arikara, and Mandan. By the time Euro-Americans arrived, the land was populated by the Omaha, Ponca, Yankton Nakota, and Teton (Brule') Lakota. The Santee Dakota were relocated to this area from Minnesota. Changes to the river brought about by human activity over the past two centuries have dramatically changed the lives of countless people. Among these are:
- Lewis and Clark - The Missouri National Recreational River corridor can serve as a microcosm of the expedition.
- Chief Standing Bear - in a landmark court case he proved that Indians were "persons" under the law,free to enjoy the rights of any other person in the land.
- Grant Marsh - Among the numerous Missouri River steamboat pilots, he was possibly the greatest ever.
The Missouri River is rich in cultural resources, in places that have a national, regional or local significance. Numerous historic sites and two archeological sites that are listed on the National Register of Historic Places are located in counties along the corridor but outside the park boundary. Three major historic sites are within the park:
- Spirit Mound - most notably assocaited with Lewis and Clark, this landmark has taken on a variety of cultural meanings that reflect the beliefs of the diverse peoples that make up the American population.
- Yankton Sioux Treaty Monument - the treaty between the United States of America and the Yankton Tribe of Sioux or Dakota Indians. Concluded at Washington, D.C. April 1856 and ratified in February 1859.
- Meridian Bridge - is notable as the first permanent river crossing in the Yankton vicinity and as one of the final links in the Meridian Highway, an early north-south route from Winnipeg, Canada, to Mexico City, Mexico.
Stories abound along the "Big Muddy", from American Indian traditions to the campfire tales of trappers, traders, and explorers, to the territory's first newspapers. These amazing stories include: